Regulation of insulin-like growth factor–dependent myoblast differentiation by Foxo forkhead transcription factors

Insulin-like growth factors promote myoblast differentiation through phosphoinositol 3-kinase and Akt signaling. Akt substrates required for myogenic differentiation are unknown. Forkhead transcription factors of the forkhead box gene, group O (Foxo) subfamily are phosphorylated in an insulin-responsive manner by phosphatidylinositol 3-kinase–dependent kinases. Phosphorylation leads to nuclear exclusion and inactivation. We show that a constitutively active Foxo1 mutant inhibits differentiation of C2C12 cells and prevents myotube differentiation induced by constitutively active Akt. In contrast, a transcriptionally inactive mutant Foxo1 partially rescues inhibition of C2C12 differentiation mediated by wortmannin, but not by rapamycin, and is able to induce aggregation-independent myogenic conversion of teratocarcinoma cells. Inhibition of Foxo expression by siRNA resulted in more efficient differentiation, associated with increased myosin expression. These observations indicate that Foxo proteins are key effectors of Akt-dependent myogenesis

Novel repressor regulates insulin sensitivity through interaction with Foxo1

This study characterizes a novel Foxo1 CoRepressor (FCoR) that regulates insulin sensitivity and energy metabolism as revealed by whole-body knockout. As target of PKA phosphorylation, FCoR modulates Foxo's acetylation known to control Foxo's biological activity

Robot-Mediated Intergenerational Childcare: Experimental Study Based on Health-Screening Task in Nursery School

The version of record of this article, first published in International Journal of Social Robotics, is available online at Publisher’s website: https://doi.org/10.1007/s12369-024-01149-7.Intergenerational interactions between children and older adults are gaining broader recognition because of their mutual benefits. However, such interactions face practical limitations owing to potential disease transmission and the poor health of older adults for face-to-face interactions. This study explores robot-mediated interactions as a potential solution to address these issues. In this study, older adults remotely controlled a social robot to perform a health-screening task for nursery school children, thereby overcoming the problems associated with face-to-face interactions while engaging in physical interactions. The results of this study suggested that the children responded favorably to the robot, and the rate of positive response increased over time. Older adults also found the task generally manageable and experienced a significant positive shift in their attitude toward children. These findings suggest that robot-mediated interactions can effectively facilitate intergenerational engagement and provide psychosocial benefits to both the parties to the engagement. This study provides valuable insights into the potential of robot-mediated interactions in childcare and other similar settings

The Soluble Tumor Necrosis Factor-Alpha Receptor Suppresses Airway Inflammation in a Murine Model of Acute Asthma

Asthma is a T helper 2 (Th2)-mediated inflammatory airway disease, characterized by airway hyperresponsiveness (AHR), chronic eosinophilic inflammation, episode of reversible bronchoconstriction, and mucus hypersecretion. In these responsies, several cytokines are considered to take part in a pivotal role. Although Th2 cytokines, including interleukin (IL)-4, IL-5 and IL-13, are important in asthma,1 tumor necrosis factor (TNF)-α has been implicated in the inflammatory response, seen in asthma.2 TNF-α is a multifunctional proinflammatory cytokine, and a chemoattractant for neutrophils and eosinophils.3 It increases the cytotoxic effect of eosinophils on endothelial cells,4 epithelial expression of adhesion molecules, such as intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1),6 and the contractile function of smooth muscles,7 and is involved in the activation of T cells.5 Howarth et al.8 reported that TNF-α concentration in bronchoalveolar lavage fluid (BALF) and TNF-α protein and messenger RNA (mRNA) expression in bronchial biopsy specimens were increased in patients with severe asthma compared those with mild disease

Constitutive Expression of Insulin Receptor Substrate (IRS)-1 Inhibits Myogenic Differentiation through Nuclear Exclusion of Foxo1 in L6 Myoblasts

Insulin-like growth factors (IGFs) are well known to play essential roles in enhancement of myogenic differentiation. In this report we showed that initial IGF-I signal activation but long-term IGF-1 signal termination are required for myogenic differentiation. L6 myoblast stably transfected with myc-epitope tagged insulin receptor substrate-1, myc-IRS-1 (L6-mIRS1) was unable to differentiate into myotubes, indicating that IRS-1 constitutive expression inhibited myogenesis. To elucidate the molecular mechanisms underlying myogenic inhibition, IGF-I signaling was examined. IGF-I treatment of control L6 cells for 18 h resulted in a marked suppression of IGF-I stimulated IRS-1 association with the p85 PI 3-kinase and suppression of activation of Akt that correlated with a down regulation of IRS-1 protein. L6-mIRS1 cells, in contrast, had sustained high levels of IRS-1 protein following 18 h of IGF-I treatment with persistent p85 PI 3-kinase association with IRS-1, Akt phosphorylation and phosphorylation of the downstream Akt substrate, Foxo1. Consistent with Foxo1 phosphorylation, Foxo1 protein was excluded from the nuclei in L6-mIRS1 cells, whereas Foxo1 was localized in the nuclei in control L6 cells during induction of differentiation. In addition, L6 cells stably expressing a dominant-interfering form of Foxo1, Δ256Foxo1 (L6-Δ256Foxo1) were unable to differentiate into myotubes. Together, these data demonstrate that IGF-I regulation of Foxo1 nuclear localization is essential for the myogenic program in L6 cells but that persistent activation of IGF-1 signaling pathways results in a negative feedback to prevent myogenesis

A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma

Memory CD4+ T cells that produce both Th2 and Th17 cytokines are increased in the blood of patients with atopic asthma and in the lungs of asthmatic mice, where they contribute to inflammation

Hyperglycemia Induces Skin Barrier Dysfunctions with Impairment of Epidermal Integrity in Non-Wounded Skin of Type 1 Diabetic Mice.

Diabetes causes skin complications, including xerosis and foot ulcers. Ulcers complicated by infections exacerbate skin conditions, and in severe cases, limb/toe amputations are required to prevent the development of sepsis. Here, we hypothesize that hyperglycemia induces skin barrier dysfunction with alterations of epidermal integrity. The effects of hyperglycemia on the epidermis were examined in streptozotocin-induced diabetic mice with/without insulin therapy. The results showed that dye leakages were prominent, and transepidermal water loss after tape stripping was exacerbated in diabetic mice. These data indicate that hyperglycemia impaired skin barrier functions. Additionally, the distribution of the protein associated with the tight junction structure, tight junction protein-1 (ZO-1), was characterized by diffuse and significantly wider expression in the diabetic mice compared to that in the control mice. In turn, epidermal cell number was significantly reduced and basal cells were irregularly aligned with ultrastructural alterations in diabetic mice. In contrast, the number of corneocytes, namely, denucleated and terminally differentiated keratinocytes significantly increased, while their sensitivity to mechanical stress was enhanced in the diabetic mice. We found that cell proliferation was significantly decreased, while apoptotic cells were comparable in the skin of diabetic mice, compared to those in the control mice. In the epidermis, Keratin 5 and keratin 14 expressions were reduced, while keratin 10 and loricrin were ectopically induced in diabetic mice. These data suggest that hyperglycemia altered keratinocyte proliferation/differentiation. Finally, these phenotypes observed in diabetic mice were mitigated by insulin treatment. Reduction in basal cell number and perturbation of the proliferation/differentiation process could be the underlying mechanisms for impaired skin barrier functions in diabetic mice

Paracrine IL-33 Stimulation Enhances Lipopolysaccharide-Mediated Macrophage Activation

BACKGROUND: IL-33, a member of the IL-1 family of cytokines, provokes Th2-type inflammation accompanied by accumulation of eosinophils through IL-33R, which consists of ST2 and IL-1RAcP. We previously demonstrated that macrophages produce IL-33 in response to LPS. Some immune responses were shown to differ between ST2-deficient mice and soluble ST2-Fc fusion protein-treated mice. Even in anti-ST2 antibody (Ab)-treated mice, the phenotypes differed between distinct Ab clones, because the characterization of such Abs (i.e., depletion, agonistic or blocking Abs) was unclear in some cases. METHODOLOGY/PRINCIPAL FINDINGS: To elucidate the precise role of IL-33, we newly generated neutralizing monoclonal Abs for IL-33. Exogenous IL-33 potentiated LPS-mediated cytokine production by macrophages. That LPS-mediated cytokine production by macrophages was suppressed by inhibition of endogenous IL-33 by the anti-IL-33 neutralizing mAbs. CONCLUSIONS/SIGNIFICANCE: Our findings suggest that LPS-mediated macrophage activation is accelerated by macrophage-derived paracrine IL-33 stimulation